CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

Panizzi, Jennifer R.; Becker-Heck, Anita; Castleman, Victoria; Al-Mutairi, Dalal A.; Liu, Yan; Loges, Niki T.; Pathak, Narendra; Austin‐Tse, Christina; Sheridan, Eamonn; Schmidts, Miriam; Olbrich, Heike; Werner, Claudius; Häffner, Karsten; Hellman, Nathan E.; Chodhari, Rahul; Gupta, Amar; Kramer-Zucker, Albrecht; Olale, Felix; Burdine, Rebecca D.; Schier, Alexander F.; O’Callaghan, Christopher; Chung, Eddie M.K.; Reinhardt, Richard; Mitchison, Hannah M.; King, Stephen M.; Omran, Heymut; Drummond, Iain A.

doi:10.1038/ng.2277

Cited by 234 publications

(201 citation statements)

References 29 publications

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“…In order to determine whether any other axonemal proteins, such as CCDC103 (King and Patel-King, 2015;Panizzi et al, 2012), were required for the 24-nm periodicity of the ODA, we also incubated ODAs with cytoplasmic microtubules that had been purified from porcine brains. The ODAs regularly bound to the porcine microtubules with 24-nm periodicity in the presence and absence of docking complex ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Docking-complex-independent alignment of Chlamydomonas outer dynein arms with 24-nm periodicity in vitro

Oda

Abe

Yanagisawa

et al. 2016

Journal of Cell Science

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The docking complex is a molecular complex necessary for assembly of outer dynein arms (ODAs) on the axonemal doublet microtubules (DMTs) in cilia and flagella. The docking complex is hypothesized to be a 24-nm molecular ruler because ODAs align along the DMTs with 24-nm periodicity. In this study, we rigorously tested this hypothesis using structural and genetic methods. We found that the ODAs can bind to DMTs and porcine microtubules with 24-nm periodicities even in the absence of the docking complex in vitro. Using cryo-electron tomography and structural labeling, we observed that the docking complex took an unexpectedly flexible conformation and did not lie along the length of DMTs. In the absence of docking complex, ODAs were released from the DMT at relatively low ionic strength conditions, suggesting that the docking complex strengthens the electrostatic interactions between the ODA and DMT. Based on these results, we conclude that the docking complex serves as a flexible stabilizer of the ODA rather than as a molecular ruler.

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Section: Resultsmentioning

confidence: 99%

Docking-complex-independent alignment of Chlamydomonas outer dynein arms with 24-nm periodicity in vitro

Oda

Abe

Yanagisawa

et al. 2016

Journal of Cell Science

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“…Motile cilia often occur in epithelial tissues to generate fluid flow, while non-motile cilia are distributed widely and are considered critical for extracellular signal reception and transduction [1,2]. Cilia play essential roles in vertebrate development, including establishment of left-right asymmetry, and brain and kidney development [3][4][5]. Disruption of cilia structure or motility is associated with a range of human disorders termed ciliopathies, such as primary ciliary dyskinesias, cystic kidney diseases and situs inversus [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

Zhang

et al. 2015

Cell Res

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Emerging data indicate that actin dynamics is associated with ciliogenesis. However, the underlying mechanism remains unclear. Here we find that nuclear distribution gene C (NudC), an Hsp90 co-chaperone, is required for actin organization and dynamics. Depletion of NudC promotes cilia elongation and increases the percentage of ciliated cells. Further results show that NudC binds to and stabilizes cofilin 1, a key regulator of actin dynamics. Knockdown of cofilin 1 also facilitates ciliogenesis. Moreover, depletion of either NudC or cofilin 1 causes similar ciliary defects in zebrafish, including curved body, pericardial edema and defective left-right asymmetry. Ectopic expression of cofilin 1 significantly reverses the phenotypes induced by NudC depletion in both cultured cells and zebrafish. Thus, our data suggest that NudC regulates actin cytoskeleton and ciliogenesis by stabilizing cofilin 1.

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“…The identification of genes involved in cytoplasmic assembly of cilia (HEATR2, DNAAF1, DNAAF2, DNAAF3, DYX1C1, CCDC103, LRRC6, ZMYND10, SPAG1, ARMC4 and C21orf59) has provided clear insights into this process [81,[85][86][87][88][89][90][91][92][93][94][95]. Defects in the assembly line can result in ODA or ODA/IDA defects.…”

Section: Genetics: Pcd Is Generally An Autosomal Recessive Disease Tmentioning

confidence: 99%

Diagnostic Methods in Primary Ciliary Dyskinesia

Lucas

Paff

Goggin

et al. 2016

Paediatric Respiratory Reviews

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Educational Aims; The reader will be able to; Describe the basis of the various diagnostic tests for PCD  Have an understanding of the strengths and limitations of each test  Understand that there is no 'gold standard' test  Understand why highly specialised centres should analyse samples and interpret results. Page 2 of 36A c c e p t e d M a n u s c r i p t  SummaryDiagnosing primary ciliary dyskinesia is difficult. With no reference standard, a combination of tests is needed; most tests require expensive equipment and specialist scientists. We review the advances in diagnostic testing over the past hundred years, with emphasis on recent advances.We particularly focus on use of high-speed video analysis, transmission electron microscopy, nasal nitric oxide and genetic testing. We discuss the international efforts that are in place to advance the evidence base for diagnostic tests.

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CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

Cited by 234 publications

References 29 publications

Docking-complex-independent alignment of Chlamydomonas outer dynein arms with 24-nm periodicity in vitro

Docking-complex-independent alignment of Chlamydomonas outer dynein arms with 24-nm periodicity in vitro

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

Diagnostic Methods in Primary Ciliary Dyskinesia

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